Skin is an organ that can be damaged by disease or injury. Skin plays a vital role of protecting the body from fluid loss and disease. Skin grafts have been prepared previously from animal skin or the patient's skin, more recently “artificial skin” formed by culturing epidermal cells. In U.S. Pat. No. 4,485,097 Bell discusses a skin-equivalent material composed of a hydrated collagen lattice with platelets and fibroblasts and cells such as keratinocytes. U.S. Pat. No. 4,060,081, to Yannas et al. discuss a multilayer membrane useful as synthetic skin formed from an insoluble non-immunogenic and a non-toxic material such as a synthetic polymer for controlling the moisture flux of the overall membrane. In U.S. Pat. No. 4,458,678, Yannas et al. discuss a process for making a skin-equivalent material wherein a fibrous lattice formed from collagen cross-linked with glycosaminoglycan is seeded with epidermal cells. However, one of the disadvantages to these artificial skins is that the matrix is formed from a “permanent” synthetic polymer. Thus, these artificial skins are not dissolvable. Additional limitations of these materials are also discussed in Yannas and Burke, J. Biomed. Mater. Res., 14, 65-81 (1980).
Classical suture technique is another method for treatment of a wound closure. However, depending on the type and/or origin of a wound as well as the location of a patient, use of tissue adhesives (e.g., glues, sealants, patches, films and the like) can be a more attractive alternative to use of sutures. In addition to an easy and fast application on a wound, other criteria for an adhesive include, but are not limited to an ability to bind to a tissue (necrosed or not, sometimes wet) with an adequate adhesion force, non-toxic material, biodegradable or resorbable material, sterilizable material, material selectively permeable to gases but impermeable to bacteria and able to control evaporative water loss, material mechanically strong enough to protect the wound and to enhance the healing process or at least not prevent it. Adhesive hemostats, based on fibrin, have been previously used and are usually constituted of fibrinogen, thrombin and factor XIII, as well as fibrinogen/photosensitizers systems. However, autologous products (which are time-consuming in emergency) or treatments of allogenic products before clinical use are needed to avoid any contamination to a patient.
Synthetic materials, e.g., polymers and hydrogels, have been developed for wound closure. For example, alkyl-cyanoacrylates (“super glues”) have been previously discussed for the repair of cornea perforations. However, monomers of these “super glues,” in particular those with short alkyl chains, can be toxic and polymerize too quickly, leading to difficulty in treating a wound. Once polymerized, the surface of the glue is rough and hard. This can cause discomfort to the patient and, for example, in case of cornea perforation treatment, a contact lens needs to be worn. Other materials have been commercialized such as “Biobrane II” (composite of polydimethylsiloxane on nylon fabric) and “Opsite” (polyurethane layer with vinyl ether coating on one side). A new polymeric hemostat (poly-N-acetyl glucosamine) has been assessed for biomedical applications such as treatment of gastric varices in order to replace cyanoacrylate (Kulling et al., Endoscopy, 30(3): S41-42 (1998)). Adhesives based on modified gelatin are also found to treat skin wounds. Photopolymerizable poly(ethylene glycol) substituted with lactate and acrylate groups are previously discussed for sealing air leaks in lung surgery.
Sealants and adhesives can help patients recover from surgery or trauma. There are medical sealant/adhesive products, CoSeal™, DuraSeal™, and Adherus®, currently existing in the market that are based on hydrogel formulations. These products comprise multiple components housed in separate containers. CoSeal™ Surgical Sealant (CoSeal™) is composed of two synthetic polyethylene glycols (PEGs), a dilute hydrogen chloride solution and a sodium phosphate/sodium carbonate solution. The DuraSeal™ Dural Sealant System consists of components for preparation of a synthetic, absorbable sealant and an applicator for delivery of the sealant to the target site the sealant is composed of two solutions, a polyethylene glycol (PEG) ester solution and a trilysine amine solution. Adherus® is composed of two solutions of polyethylene glycol (PEG) ester NHS derivative and polyalkyleneimine.
Fibrin glues are also sold in packaging and applicator systems that are similar to those used for CoSeal™ and DuraSeal™. One example is Baxter's Tisseel. Tisseel VH (Fibrin Sealant) consists of a two-component fibrin biomatrix that offers highly concentrated human fibrinogen to seal tissue and stop diffuse bleeding. However, all of the existing wound dressing, sealants or glues cannot be dissolved after application to the tissue site. That is, they have to be removed by mechanical debridement and/or surgical incision, if needed.
Hydrogels are one class of biomaterials currently used in medical and clinical applications, including sealing of wounds. See, e.g., Ruan, L. et al., PNAS 2009, 106, 5105-5110; Aboushwareb, T. et al. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2009, 90B, 45-54; Hattori, H. et al., Annals of Biomedical Engineering, 2010, 38, 3724-3732; and Luo, Z. et al. Biomaterials, 2011, 32, 2013-2020. Hydrogels can be used as coatings (e.g. biosensors, catheters, and sutures), as “homogeneous” materials (e.g. contact lenses, burn dressings, and dentures), and as devices (e.g. artificial organs and drug delivery systems) (Peppas, N. A. Hydrogel in Medicine and Pharmacy, Vol I and II 1987. Wichterle, O.; Lim, D. Nature 1960, 185, 117-118. Ottenbrite, R. M.; Huang, S. J.; Park, K. Hydrogels and Biodegradable polymers for Bioapplications 1994; Vol. 627, pp 268).
Synthetic hydrogel based hemostats/sealants can offer a number of advantages because the chemical composition of the hydrogels can be tuned for various properties, e.g., but not limited to, water content, sensitivity to environmental conditions (e.g., but not limited to, pH, temperature, solvent, stress), softness, tissue adhesion, rubbery consistency, mechanical, degradation, and swelling properties. However, we are not aware of a hydrogel reported, e.g., for emergency care, where a hydrogel is applied to a wound and can be subsequently removed to allow for definitive surgical care at the hospital.
A desirable or useful hydrogel or sealant system, e.g., for trauma scenarios sustained in military injuries or in rural or wilderness settings, should: (1) provide consistent hemostasis for several hours; (2) adhere to the tissue; (3) be easily applied; (4) enable controlled dissolution of the sealant in the surgical theatre setting to allow for gradual wound re-exposure during definitive surgical care. Alam, H. B. et al. Military Medicine 2005, 170, 63-69. However, we are not aware of a dissolution capability present in any available wound hemostatic system as discussed above. Indeed, removal of a clotting agent or dressing from a wound is currently performed via mechanical debridement and/or surgical excision, which could potentially cause additional damage to tissue at and/or surrounding the wound. Accordingly, there is a need for an improved wound dressing or sealant composition, e.g., for use in wound management.